Project II: Gastrointestinal nutrient signals The present obesity epidemic highlights the fact that many individuals are unable to limit adequately their intakes of calories when exposed to modern Western diets. Given the urgency of this health problem, it is problematic that so little is known about gastrointestinal (Gl) nutrient sensing that might be augmented to help limit ingestion. The long-term objective of the present proposal is to characterize and analyze more fully such post-oral or post-ingestive sensing abilities of the Gl tract. Traditionally, nutritional neuroscience has had few experimental strategies for analyzing nutrient detection in the gut, and some of those techniques have not readily linked putative signals to the control of ingestion. To help address these limitations, we have recently introduced a new testing paradigm that assesses whether a particular macronutrient or defined stimulus property of food in the Gl tract can be used to control feeding decisions. This "intestinal taste aversion paradigm" pairs a Gl infusion of a novel nutrient with subsequent malaise to train animals. After conditioning, the animals are then given oral intake tests with the nutrient. This protocol provides a behavioral assay for determining whether an animal can detect, and discriminate between, particular macronutrients in its Gl tract. Such visceral sensory psychophysical information can indicate which features of nutrients are salient and effective in short-term control of ingestion and which features are poorly detected or perhaps go undetected. The present proposal seeks to characterize the neural mechanisms of this intestinal taste aversion and to use the procedure to assess the nutrient-detecting proficiencies of the gut: Specific Aim 1 is to determine where in the Gl tract or organs of metabolism, and by what pathways, different nutrient stimuli that influence intake are detected. Specific Aim 2 is to determine the most effective stimulus and protocol parameters for the paradigm in order to optimize such nutrient feedback and characterize its mechanisms. Specific Aim 3 is to use additional stimuli and generalization tests to determine what discriminations can be made about gastrointestinal stimuli and how broadly or narrowly tuned the post-ingestive nutrient detectors are. Specific Aim 4 is to assess the relationship between learning about post-ingestive nutrient stimuli and learning about nutrient cues detected by mouth. The proposed research program has implications for understanding and treating a variety of eating and metabolic disorders including anorexia, bulimia, and food allergies as well as, of course, obesity. Dr. Rowley (PI) and Dr. Davidson will direct this research in collaboration with Dr. Robert Phillips from the Department of Psychological Sciences at Purdue University.